Department of Pharmacology and Toxicology, College of Pharmacology, King Saud University, P.O. Box 2457, Riyadh, 11451, Kingdom of Saudi Arabia,
Cardiovasc Toxicol. 2015 Jan;15(1):41-51. doi: 10.1007/s12012-014-9266-y.
Sunitinib (SUN) is a multi-targeted tyrosine kinase inhibitor used for the treatment of gastrointestinal stromal tumors and renal cell carcinoma. Cardiotoxicity has been reported as a significant side effect associated with the SUN treatment, yet the mechanism is poorly understood. The main purpose of this study was to investigate the potential effects of SUN on cardiac hypertrophic genes and the role of mitogen-activated protein kinases (MAPKs) signaling pathway in rat cardiomyocyte H9c2 cell line. In the present study, real-time quantitative polymerase chain reaction showed that the treatment of H9c2 cells with increasing concentrations of SUN (0, 1, 2.5, and 5 µM) significantly induced hypertrophic gene markers, such as brain natriuretic peptides (BNP) and myosin heavy chain (β-MHC and α-MHC) in concentration- and time-dependent manners. The onset of mRNA induction was observed as early as 9 h and remained elevated for at least 18 h after treatment with SUN 5 µM. At the protein level, Western blot analysis showed that SUN increased BNP and β-MHC, while it inhibited α-MHC protein levels in a concentration-dependent manner. These SUN-mediated effects were associated with increase in cell size and hypertrophy by approximately 70 % at the highest concentration, 5 µM. Importantly, inhibition of the MAPK signaling pathway using SB203580 (p38 MAPK inhibitor), U0126 (extracellular signal-regulated kinase inhibitor), and SP600125 (c-Jun NH2-terminal kinase inhibitor) significantly potentiated the SUN-induced BNP and β-MHC mRNA levels, but did alter the α-MHC level. Whereas at the protein level, MAPK inhibitors generally decreased the SUN-induced BNP, whereas only SB and U0 increased β-MHC protein levels with no effect on α-MHC, which were associated with a significant decrease in cell size. Together, these results indicate that SUN induced hypertrophic gene expression through MAPK-dependent mechanisms.
舒尼替尼（Sunitinib）是一种多靶点酪氨酸激酶抑制剂，用于治疗胃肠道间质瘤和肾细胞癌。已有报道称，舒尼替尼治疗会引起心脏毒性，但其机制尚不清楚。本研究的主要目的是研究舒尼替尼对心脏肥厚基因的潜在影响，以及丝裂原活化蛋白激酶（MAPKs）信号通路在大鼠心肌细胞 H9c2 细胞系中的作用。在本研究中，实时定量聚合酶链反应显示，随着舒尼替尼浓度（0、1、2.5 和 5 µM）的增加，H9c2 细胞中与心脏肥厚相关的基因标志物，如脑钠肽（BNP）和肌球蛋白重链（β-MHC 和 α-MHC）的表达呈浓度和时间依赖性增加。mRNA 诱导的起始时间早在 9 小时，并且在用舒尼替尼 5 µM 处理后至少 18 小时仍保持升高。在蛋白质水平上，Western blot 分析显示舒尼替尼增加了 BNP 和 β-MHC，同时以浓度依赖的方式抑制了 α-MHC 蛋白水平。舒尼替尼介导的这些作用与细胞大小的增加有关，在最高浓度 5 µM 时，细胞大小增加了约 70%，发生了肥大。重要的是，使用 SB203580（p38 MAPK 抑制剂）、U0126（细胞外信号调节激酶抑制剂）和 SP600125（c-Jun NH2-末端激酶抑制剂）抑制 MAPK 信号通路显著增强了舒尼替尼诱导的 BNP 和 β-MHC mRNA 水平，但并未改变 α-MHC 水平。然而，在蛋白质水平上，MAPK 抑制剂通常降低了舒尼替尼诱导的 BNP，而只有 SB 和 U0 增加了 β-MHC 蛋白水平，对 α-MHC 没有影响，这与细胞大小的显著减小有关。总之，这些结果表明舒尼替尼通过 MAPK 依赖性机制诱导了肥厚基因的表达。
